title: Fluoroquinolone susceptibility in Mycobacterium tuberculosis after pre-diagnosis exposure to older- versus newer-generation fluoroquinolones.
abstract: Fluoroquinolone exposure before tuberculosis (TB) diagnosis is common. We anticipated that exposure to older-generation fluoroquinolones is associated with greater fluoroquinolone MICs in Mycobacterium tuberculosis than exposure to newer agents. A nested case-control study was performed among newly diagnosed TB patients reported to the Tennessee Department of Health (January 2002-December 2009). Each fluoroquinolone-resistant case (n=25) was matched to two fluoroquinolone-susceptible controls (n=50). Ciprofloxacin and ofloxacin were classified as older-generation fluoroquinolones; levofloxacin, moxifloxacin and gatifloxacin were considered newer agents. There was no difference between median ofloxacin MIC for isolates from 9 patients exposed only to older fluoroquinolones, 25 exposed only to newer fluoroquinolones, 6 exposed to both and 35 fluoroquinolone-unexposed patients (Kruskal-Wallis, P=0.35). Using multivariate proportional odds logistic regression adjusting for age and sex, duration of exposure to newer fluoroquinolones was independently associated with higher MIC (OR=1.79, 95% CI 1.22-2.64), but duration of exposure to older fluoroquinolones was not (OR=0.94, 95% CI 0.50-1.78). Isolates from patients exposed only to newer fluoroquinolones tended to have mutations at gyrA codons 90, 91 or 94 more frequently than those exposed only to older fluoroquinolones (44% vs. 11%). We were surprised to find that duration of exposure to newer fluoroquinolones, but not older ones, was independently associated with higher ofloxacin MIC. This suggests that the mutant selection window lower boundary is likely to have clinical relevance; caution is warranted when newer fluoroquinolones are prescribed to patients with TB risk factors.
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA. yuri.vanderheijden@vanderbilt.edu
authors.forename: Yuri F
authors.initials: YF
authors.lastname: van der Heijden
authors.forename: Fernanda
authors.initials: F
authors.lastname: Maruri
authors.forename: Amondrea
authors.initials: A
authors.lastname: Blackman
authors.forename: Ed
authors.initials: E
authors.lastname: Mitchel
authors.forename: Aihua
authors.initials: A
authors.lastname: Bian
authors.forename: Ayumi K
authors.initials: AK
authors.lastname: Shintani
authors.forename: Svetlana
authors.initials: S
authors.lastname: Eden
authors.forename: Jon V
authors.initials: JV
authors.lastname: Warkentin
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Sterling
mesh_terms: D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001372:Aza Compounds / Q000627:therapeutic use; D016022:Case-Control Studies; D002939:Ciprofloxacin / Q000627:therapeutic use; D027081:DNA Gyrase / Q000235:genetics; D024881:Drug Resistance, Bacterial; D005260:Female; D024841:Fluoroquinolones / Q000494:pharmacology / Q000627:therapeutic use*; D000077734:Gatifloxacin; D006801:Humans; D064704:Levofloxacin / Q000627:therapeutic use; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D000077266:Moxifloxacin; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D015242:Ofloxacin / Q000627:therapeutic use; D011804:Quinolines / Q000627:therapeutic use; D014376:Tuberculosis / Q000175:diagnosis / Q000188:drug therapy*
chemical_list: D000900:Anti-Bacterial Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D011804:Quinolines; D002939:Ciprofloxacin; D064704:Levofloxacin; D015242:Ofloxacin; D027081:DNA Gyrase; D000077734:Gatifloxacin; D000077266:Moxifloxacin
keywords: Ciprofloxacin; Drug-resistant tuberculosis; Genotypic resistance; Levofloxacin; Moxifloxacin